The development of bifunctional therapeutics has great potential to augment combination therapy strategies. A bifunctional therapeutic can provide the benefit of a combination therapy by modulating 2 different pathways with one therapeutic entity. In addition, bifunctional therapeutics may also benefit from synergies between pathways and demonstrate increased activity compared to mono-functional agents. Furthermore, bifunctional therapeutics can provide benefits in terms of reduced manufacturing, storage, and shipping costs, as well as reducing the number of therapies given to the patient and simplifying dosage regimes.
IGF1 R is a transmembrane heterotetrameric protein, which has 2 extracellular chains and 2 membrane-spanning β-chains in a disulfide-linked (β-α-α-β) configuration. IGF1R binds IGF1 with high affinity. IGF1 is a 70 amino acid peptide that is mainly produced by the liver in response to growth hormone stimulation but can be synthesized by almost any tissue in the body and circulates in serum to concentrations of 100-200 ng/mL. IGF1R signalling may play a role in multiple tumour types and is specifically implicated in lung cancer. For instance, elevated plasma levels of IGF1 are associated with an increased risk of lung cancer. Additionally, IGF1, IGF2, and IGF1R are expressed by normal lung cells but over-expressed by lung cancer cells. IGF1R signalling has also been implicated in breast cancer, prostate cancer, colorectal cancer, sarcoma, multiple myeloma, and other malignancies. WO02053596, WO2005016967, WO2005005635, and WO2009032145 disclose IGF1R antibodies and antigen-binding portions thereof.
Angiopoietin-1 (Ang1) and Angiopoietin-2 (Ang2) mediate the angiogenesis process as ligands of the endothelial cell receptor Tie2, along with VEGF and other angiogenic regulators. Ang1 stimulates the phosphorylation of Tie2, recruits pericytes to newly-formed blood vessels, and promotes their maturation. Ang2 is known to be angiogenic and over-expressed in many cancers. Ang2 competes with Ang1 for binding of Tie2, promotes the dissociation of pericytes, and results in unstable blood vessels. In the presence of VEGF and other angiogenic factors, endothelial cells in these unstable vessels proliferate and migrate to form new blood vessels.
About 50% of patients with solid tumours have increased expression of Ang2 but the levels of Ang2 in cancer tissues are highly variable. Higher Ang2 expression is clearly correlated with poor survival, later stage disease and more invasive cancers. A lower ratio between Ang1 and Ang2 has also been correlated with a poor prognosis for ovarian cancer. Tie2 expression is reported to be up-regulated in hepatocellular carcinoma, astrocytoma, Kaposi's sarcoma, cutaneous angiosarcoma, and non-small cell lung carcinoma. Tie2 is over-expressed on the blood vessels of many tumours. Tie2 expressing monocytes contribute to the formation of tumour blood vessels. Newly published data demonstrate that specifically sequestering Ang2 can inhibit tumour growth and cause staged tumours to regress. WO2008056346 discloses Ang2-binding peptides.
Targeting both IGF1R and Ang2 in the same therapy may prove to be an effective tool for oncologists to use in multiple treatment settings. Such approaches have been postulated (for example, in WO2009088805 and WO2010040508), but none have been approved to date. There therefore exists a need to provide alternative oncology therapies targeting both IGR-1R and Ang2.
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